Nontoxic nanoparticle can deliver and track drugs

A nontoxic nanoparticle developed by Penn State researchers is proving to be an all-around effective delivery system for both therapeutic drugs and the fluorescent dyes that can track their delivery.

In a recent online issue of Nano Letters, an interdisciplinary group of materials scientists, chemists, bioengineers, physicists, and pharmacologists show that calcium phosphate particles ranging in size from 20 to 50 nanometers will successfully enter cells and dissolve harmlessly, releasing their cargo of drugs or dye.

Peter Butler, associate professor of bioengineering, and his students used high-speed lasers to measure the size of fluorescent dye-containing particles from their diffusion in solution.

“We use a technique called time correlated single photon counting,” Butler says. “This uses pulses of laser light to read the time, on the order of nanoseconds, that molecules fluoresce.”

With this method, his group was able to measure the size of the particles and their dispersion in solution, in this case a phosphate-buffered saline that is used as a simple model for blood.

“What we did in this study was to change the original neutral pH of the solution, which is similar to blood, to a more acidic environment, such as around solid tumors and in the parts of the cell that collect the nanoparticles-containing fluid immediately outside the cell membrane and bring it into the cell. When we lower the pH, the acidic environment dissolves the calcium phosphate particle,” he adds.

“We can see that the size of the particles gets very small, essentially down to the size of the free dye that was inside the particles. That gives us evidence that this pH change can be used as a mechanism to release any drug that is encapsulated in the particle,” Butler explains.

Although the primary use envisioned for these particles is for targeted cancer therapy, Butler’s group is interested in their ability to deliver various drugs that have been shown to inhibit cell growth associated with vascular disease.

Several drugs have been shown in cultures to be promising for reducing hardening of the arteries and narrowing of blood vessels after balloon angioplasty. The problem has been in delivering any of these drugs to a target, Butler says.

Ceramide, a chemotherapeutic molecule that initiates cell death in cancer cells, has the ability to slow growth in healthy cells.

Mark Kester, professor of pharmacology, and Jong Yun, associate professor of pharmacology, both at Penn State College of Medicine, have optimized ceramide for both cancer and vascular disease.

Their groups found that by using human vascular smooth muscle cells in vitro, ceramide encapsulated in calcium phosphate nanoparticles reduced growth of muscle cells by up to 80 percent at a dose 25 times lower than ceramide administered freely, without damaging the cells.

The calcium phosphate nanoparticles were developed by James Adair, professor of materials science and engineering, and his students. The nanoparticles have several benefits other drug delivery systems do not, according to lead author Thomas Morgan, graduate student in chemistry.

Unlike quantum dots, which are composed of toxic metals, calcium phosphate is a safe, naturally occurring mineral that already is present in substantial amounts in the bloodstream.

“What distinguishes our method are smaller particles (for uptake into cells), no agglomeration (particles are dispersed evenly in solution), and that we put drugs or dyes inside the particle where they are protected, rather than on the surface,” says Morgan. “For reasons we don’t yet understand, fluorescent dyes encapsulated within our nanoparticles are four times brighter than free dyes.

“Drugs and dyes are expensive,” he continues, “but an advantage of encapsulation is that you need much less of them. We can make high concentrations in the lab, and dilute them way down and still be effective. We even believe we can combine drug and dye delivery for simultaneous tracking and treatment. That’s one of the things we are currently working on.”

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Other researchers on the project are graduate students Erhan Altinoglu and Amra Tabakovic, materials science and engineering, and former group member, Sara Rouse, Ph.D. in materials; graduate students Hari Muddana and Tristan Tabouillot, bioengineering; Timothy Russin, physics; Sriram Shanmugavelandy, pharmacology; and Peter Eklund, distinguished professor of physics and materials science and engineering.

Most of the researchers are affiliated with Penn State’s Materials Research Institute, which supports more than 200 faculty groups involved in materials research at Penn State. More information is at www.mri.psu.edu

Support for this research was provided by National Science Foundation, NASA, Keystone Nano Inc. and NIH-NHLBI.

Thin films of a new polymer developed at Penn State change temperature in response to changing electric fields. The Penn State researchers, who reported the new material in Science last week, say that it could lead to new technologies for cooling computer chips and to environmentally friendly refrigerators.

Changing the electric field rearranges the atoms in the polymer, which in turn govern its temperature; this is called the electrocaloric effect. In a cooling device, a voltage would be applied to the material, which would then be brought in contact with whatever it’s intended to cool. The material would heat up, passing its energy to a heat sink or releasing it into the atmosphere. Reducing the electric field would bring the polymer back to a low temperature so that it could be reused.

In a 2006 paper in Science, Cambridge University researchers led by materials scientist Neil Mathurdescribed ceramic materials that also exhibited the electrocaloric effect, but only at temperatures of about 220 °C. The operating temperature of a computer chip is significantly lower–usually somewhere around 85 °C–and a kitchen refrigerator would have to operate at lower temperatures still. The Penn State polymer shows the same 12-degree swing that the ceramics did, but it works at a relatively low 55 °C.

The polymer also absorbs heat better. “In a cooling device, besides temperature change, you also need to know how much heat it can absorb from places you need to cool,” says Qiming Zhang, an electrical-engineering professor at Penn State, who led the new work. The polymer, Zhang says, can absorb seven times as much heat as the ceramic.

Cool spool: Films of a specially designed polymer, just 0.4 to 2.0 micrometers thick, can get colder or hotter by 12 °C when an electric field is removed or applied across them.

Researchers generate hydrogen without the carbon footprint

A greener, less expensive method to produce hydrogen for fuel may eventually be possible with the help of water, solar energy and nanotube diodes that use the entire spectrum of the sun’s energy, according to Penn State researchers.

“Other researchers have developed ways to produce hydrogen with mind-boggling efficiency, but their approaches are very high cost,” says Craig A. Grimes, professor of electrical engineering. “We are working toward something that is cost effective.”

Currently, the steam reforming of natural gas produces most of our hydrogen. As a fuel source, this produces two problems. The process uses natural gas and so does not reduce reliance on fossil fuels; and, because one byproduct is carbon dioxide, the process contributes to the carbon dioxide in the atmosphere, the carbon footprint.

Grimes’ process splits water into its two components, hydrogen and oxygen, and collects the products separately using commonly available titanium and copper. Splitting water for hydrogen production is an old and proven method, but in its conventional form, it requires previously generated electricity. Photolysis of water solar splitting of water has also been explored, but is not a commercial method yet.

Grimes and his team produce hydrogen from solar energy, using two different groups of nanotubes in a photoelectrochemical diode. They report in the July issue of Nano Lettersthat using incident sunlight, “such photocorrosion-stable diodes generate a photocurrent of approximately 0.25 milliampere per centimeter square, at a photoconversion efficiency of 0.30 percent.”

“It seems that nanotube geometry is the best geometry for production of hydrogen from photolysis of water,” says Grimes

In Grimes’ photoelectrochemical diode, one side is a nanotube array of electron donor material – n-type material – titanium dioxide, and the other is a nanotube array that has holes that accept electrons – p-type material – cuprous oxide titanium dioxide mixture. P and n-type materials are common in the semiconductor industry. Grimes has been making n-type nanotube arrays from titanium by sputtering titanium onto a surface, anodizing the titanium with electricity to form titanium dioxide and then annealing the material to form the nanotubes used in other solar applications. He makes the cuprous oxide titanium dioxide nanotube array in the same way and can alter the proportions of each metal.

While titanium dioxide is very absorbing in the ultraviolet portion of the sun’s spectrum, many p-type materials are unstable in sunlight and damaged by ultraviolet light, they photo-corrode. To solve this problem, the researchers made the titanium dioxide side of the diode transparent to visible light by adding iron and exposed this side of the diode to natural sunlight. The titanium dioxide nanotubes soak up the ultraviolet between 300 and 400 nanometers. The light then passes to the copper titanium side of the diode where visible light from 400 to 885 nanometers is used, covering the light spectrum.

The photoelectrochemical diodes function the same way that green leaves do, only not quite as well. They convert the energy from the sun into electrical energy that then breaks up water molecules. The titanium dioxide side of the diode produces oxygen and the copper titanium side produces hydrogen.

Although 0.30 percent efficiency is low, Grimes notes that this is just a first go and that the device can be readily optimized.

“These devices are inexpensive and because they are photo-stable could last for years,” says Grimes. “I believe that efficiencies of 5 to 10 percent are reasonable.”

Grimes is now working with an electroplating method of manufacturing the nanotubes, which will be faster and easier.

Physicists at Penn State and the Raman Research Institute in India have discovered such a mechanism by which information can be recovered from black holes.

They suggest that singularities do not exist in the real world. “Information only appears to be lost because we have been looking at a restricted part of the true quantum-mechanical space-time,” said Madhavan Varadarajan, a professor at the Raman Research Institute. “Once you consider quantum gravity, then space-time becomes much larger and there is room for information to reappear in the distant future on the other side of what was first thought to be the end of space-time.”